DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendment/Status of Claims
Receipt of Arguments/Remarks filed on 07/29/2026 is acknowledged. Claim 90 was cancelled. Claims 51 and 91 were amended.
Applicant’s election without traverse of “a composition comprising at least three harmonized RNA species”, consistent with Examples 2 and 5 and studies shown in Fig. 6 in the reply filed on 02/17/2026 is acknowledged.
The Examiner withdrawn the species election in the office action dated 047/29/2026 due to the cited art teaching at least two harmonized RNA species.
Claims 55,71-89 and 91-94 are pending an under examination.
Priority
This application is a CON of 16/762,081 filed 05/06/2020 PAT 11,692,002 which is a 371 of PCT/EP2018/080692, filed 11/08/2018. This application also claims foreign priority to PCT/EP2017/078647, filed 11/08/2017, as reflected by the most recent filing receipt.
Withdrawn Objections and Rejections
Applicant’s arguments and amendments, see page 8, filed 07/29/2026, with respect to the objections to the abstract and objections to the drawings have been fully considered and are persuasive due to the amendments to the abstract and drawings correcting the issues. The objection to the abstract and drawings has been withdrawn.
Applicant’s arguments and amendments, see pages 8-9, filed 07/29/2026, with respect to the 35 U.S.C. 112(b) rejection of claims 55 and 71-94 and the 35 U.S.C. 112(d) rejection of claim 90 have been fully considered and are persuasive due to the amendments to claim 55 regarding the 35 U.S.C. 112(b) rejection and the cancelation of claim 90 for the 35 U.S.C. 112(d) rejection. The 35 U.S.C. 112(b) and 112(d) rejections have been withdrawn.
The terminal disclaimer filed on 07/29/2026 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of U.S. Patent No. 11,692,002 has been reviewed and is accepted. The terminal disclaimer has been recorded. The Double Patenting rejection over claims of U.S. Patent No. 11,692,002 has been withdrawn.
Modified Rejections-Necessitated by Amendment
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Interpretation
The instant specification does not provide a definition of “harmonized RNA species”. Example 2.1 of the instant specification discloses that sequence adaptation was performed such that the encoded amino acid sequence was unchanged, either by exploiting the degeneracy of the genetic code or by introducing an adenine stretch into the polyA tail or the UTR of the RNA molecule species (page 78). In addition, page 78 states in order to harmonize the retention times of a RNA molecule species encoding different HA antigens, GC-optimized DNA sequence encoding different HA proteins of Influenza B were adapted by increasing the number of A nucleotides by adapting the coding sequence, by elongating the polyA sequence or by introducing additional A nucleotides into the UTR region. Example 4 discloses optimizing GC DNA sequence encoding different influenza NA proteins by decreasing the number of A nucleotides by altering the coding sequence. Therefore, art that teaches a composition comprising at least two RNA species having the recited structure of the instant claims and having an increased or decreased number of A nucleotides reads on claim 55. The reference does not need to explicitly teach the RNA as “harmonized RNA species” as this does not appear to be a term used in the art.
Claims 55,71-73,75 and 78-83 are rejected under 35 U.S.C. 103 as being unpatentable over Ciaramella et al. (WO 2017070620, Published 27 April 2017) in view of CureVac (US 20100239608, Published 23 Sept 2010), and Gilar et al. (Journal of Chromatography A, 958 (2002) 167-182).
Regarding claims 55,71,78 and 79, Ciaramella et al. teach RNA (e.g., mRNA) vaccines which are multivalent (page 10, line 28), including influenza vaccines comprising multiple RNA polynucleotides, each encoding a single antigenic polypeptide (page 47, lines 5-8). Ciaramella et al. teach influenza vaccines comprising one or more RNA polynucleotides having an open reading frame encoding a hemagglutinin protein and a pharmaceutically acceptable carrier or excipient (page 23, lines 33-35), and teach embodiments where the RNA polynucleotide further encodes neuraminidase protein (page 24, line 2). Ciaramella et al. teach the basic components of an mRNA molecule typically include at least one coding region, a 5’UTR, a 3’UTR, a 5’ cap and a poly-A tail (page 39, lines 14-15). Ciaramella et al. teach naturally-occurring eukaryotic mRNA molecules have been found to contain stabilizing elements, including, but not limited to untranslated regions (UTR) at their 5 '-end (5'UTR) and/or at their 3'-end (3 'UTR), in addition to other structural features, such as a 5'- cap structure or a 3'-poly(A) tail (page 73, lines 16-19), and a polyA tail may contain 10-300 adenosine monophosphates, and functions to protect mRNA from enzymatic degradation in the cytoplasm, aids in transcription termination, export of the mRNA from the nucleus and translation (page 65, lines 3-9). Ciaramella et al. teach the polynucleotide includes 200-3000 nucleotides (page 65, line 10).
Ciaramella et al. do not teach the number of A and U nucleotides have been altered in the RNA encoding each of the influenza polypeptides, or wherein harmonized RNA species have retention times that cause the at least two RNA species to co-elute as a single, overlaid product peak in reversed-phase HPLC for co-purification and/or co-analysis.
Before the effective filing date, CureVac taught the object of the present invention is to provide a new system for gene therapy and genetic vaccination that overcomes the disadvantages associated with the properties of DNA therapeutic agents and DNA vaccines and that increases the effectiveness of therapeutic agents based on RNA species (paragraph 0019). CureVac taught a pharmaceutical composition containing at least one modified mRNA of the present invention and a pharmaceutically compatible carrier and/or vehicle are provided. The modified mRNA encodes at least one biologically active or antigenic peptide or polypeptide, wherein the sequence of the mRNA comprises at least one modification as set forth herein below as compared to the wild type mRNA. Such modifications may be located in the region coding for the at least one peptide or polypeptide, or in untranslated regions (paragraph 0021).
CureVac taught the G/C content of the region of the modified mRNA coding for the peptide or polypeptide is increased relative to that of the G/C content of the coding region of the wild type mRNA coding for the peptide or polypeptide. The encoded amino acid sequence, however, remains unchanged compared to the wild type (i.e. silent with respect to the encoded amino acid sequence) (paragraph 0022), and this modification is based on the fact that, for efficient translation of an mRNA, the sequence of the region of the mRNA to be translated is essential. In this connection the composition and the sequence of the various nucleotides play an important role. In particular sequences with an increased G (guanosine)/C (cytosine) content are more stable than sequences with an increased A (adenosine)/U (uracil) content. In accordance with the invention, the codons are varied compared to the wild type mRNA, while maintaining the translated amino acid sequence, so that they contain increased amounts of G/C nucleotides (paragraph 0023).
CureVac taught preferably the G/C content of the region of the modified mRNA coding for the peptide or polypeptide is increased by at least 7%, more preferably by at least 15%, and particularly preferably by at least 20% compared to the G/C content of the coded region of the wild type mRNA encoding for the polypeptide (paragraph 0029). CureVac also taught for efficient translation of the mRNA a productive binding of the ribosomes to the ribosome binding site [Kozak sequence: GCCGCCACCAUGG (SEQ ID NO: 13), the AUG forms the start codon] is generally required. In this regard it has been established that an increased A/U content around this site facilitates more efficient ribosome binding to the mRNA (paragraph 0045).
Additionally, before the effective filing date, Gilar et al. taught that oligonucleotide retention is affected by its nucleotide composition, and developed a mathematical model for the prediction of oligonucleotide retention from sequence and length (Abstract). Gilar et al. taught reversed-phase HPLC purification as a popular technique for oligonucleotide purification (page 168, left column). Gilar et al. taught that the separation of heterooligonucleotides in an RP-HPLC system could be challenging due to the different hydrophobicities of the A, C, T and G bases, and oligonucleotides of the same length but different sequence may exhibit different retention, which can be advantageous as well as challenging for some applications (page 174, left column).
Gilar et al. found that the hydrophobicity contribution to the oligonucleotide retention increases in order C,G,A,T, which is in agreement with earlier published data (page 174, right column), and the oligonucleotide sequence has an impact not only on retention, but also on the success of the target product separation from failure sequences (page 178, right column). Gilar et al. taught according to the experimental data, the hydrophobic contribution of C and G mononucleotides to the oligonucleotide retention is less significant than A and T. Therefore, peak retention for a heterooligonucleotide ladder may be affected by its nucleotide sequence (page 178, right column).
Gilar et al. taught the proposed retention model can, to a certain extent, predict the peak spacing taking into account that the change of oligonucleotide retention with the addition (or loss) of a single mononucleotide correlates with the nucleotide hydrophobicity C,G,A,T. In other words, the addition of C or G does not increase oligonucleotide retention as dramatically as the addition of A and particularly T (pages 179-180).
Regarding claim 72, Ciaramella et al. also teach a vaccine comprising at least one RNA polynucleotide having an open reading frame encoding a HA protein, or immunogenic fragment thereof, and a NA protein, or immunogenic fragment thereof, obtained from influenza virus (page 25 lines 30-33).
Regarding claim 73, Ciaramella et al. teach a vaccine comprising at least one RNA having an ORF encoding a HA protein (HA or derivatives thereof comprising antigenic sequences from HA1 and/or HA2) (page 30, lines 15-17).
Regarding claim 75, Ciaramella et al. teach the RNA vaccines of the present disclosure comprise 2-10 or more RNA polynucleotides each of which encodes a different antigenic polypeptide and may be selected from any of the influenza antigenic polypeptides described herein (page 47, lines 15-20).
Regarding claims 80 and 81, Ciaramella et al. teach the influenza RNA vaccine is formulated in a lipid-polycation complex, referred to as a cationic lipid nanoparticle (page 75, lines 8-10), and an influenza RNA (e.g., mRNA) vaccine of any one of the foregoing paragraphs formulated in a nanoparticle (e.g., a lipid nanoparticle) (page 10, lines 13-14). Ciaramella et al. teach the surprising finding that lipid nanoparticle (LNP) formulations significantly enhance the effectiveness of mRNA vaccines, including chemically modified and unmodified mRNA vaccines. The efficacy of mRNA vaccines formulated in LNP was examined in vivo using several distinct antigens. The results presented herein demonstrate the unexpected superior efficacy of the mRNA vaccines formulated in LNP over other commercially available vaccines. In addition to providing an enhanced immune response, the formulations of the invention generate a more rapid immune response with fewer doses of antigen than other vaccines tested. The mRNA-LNP formulations of the invention also produce quantitatively and qualitatively better immune responses than vaccines formulated in a different carriers (page 37, lines 29-34 and page 38, lines 1-4).
Regarding claims 82-83, Ciaramella et al. teaches a vaccine that includes at least one RNA polynucleotide having an ORF encoding at least one influenza antigenic polypeptide, wherein at least 80% of the uracil in the open reading frame having a chemical modification, and embodiments where 100% of the uracil in the ORF have a N1-methylpseudouridine in the 5-position of the uracil (page 9, lines 4-14). Ciaramella et al. teach the RNA vaccines of the present disclosure comprise 2-10 or more RNA polynucleotides each of which encodes a different antigenic polypeptide and may be selected from any of the influenza antigenic polypeptides described herein (page 47, lines 15-20).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to have modified each of the RNAs encoding each influenza antigen in the vaccine of Ciaramella et al. with the teachings of CureVac regarding suggesting modifying the G/C content or A/U content and the teachings of Gilar et al. regarding that reversed-phase HPLC oligonucleotide retention is affected by its nucleotide composition in order to provide a multivalent RNA vaccine wherein each RNA encoding the influenza polypeptide antigens has modified G/C or A/U content in order to modify oligonucleotide peak retention in reversed phase HPLC based on the number of A and T nucleotides with a reasonable expectation of success. There would be a reasonable expectation of success, because CureVac also pertains to RNA vaccines, and because Gilar et al. pertains to reversed-phase HPLC of oligonucleotides and analysis and prediction of retention based on various factors including nucleotide sequence.
One of ordinary skill in the art would have been motivated to do so because CureVac taught a new system for genetic vaccination that overcomes the disadvantages associated with the properties of DNA therapeutic agents and DNA vaccines and that increases the effectiveness of therapeutic agents based on RNA species (paragraph 0019). CureVac taught the G/C content of the region of the modified mRNA coding for the peptide or polypeptide is increased relative to that of the G/C content of the coding region of the wild type mRNA coding for the peptide or polypeptide, while the encoded amino acid sequence remains unchanged compared to the wild type and particular sequences with an increased G (guanosine)/C (cytosine) content are more stable than sequences with an increased A (adenosine)/U (uracil) content. CureVac also taught for efficient translation of the mRNA a productive binding of the ribosomes to the ribosome binding site [Kozak sequence: GCCGCCACCAUGG (SEQ ID NO: 13), the AUG forms the start codon] is generally required. In this regard it has been established that an increased A/U content around this site facilitates more efficient ribosome binding to the mRNA (paragraph 0045).
In addition, one of ordinary skill in the art would have been motivated by the teachings of Gilar et al. regarding oligonucleotide purification and analysis by reversed-phase HPLC and that Gilar et al. found that the hydrophobicity contribution to the oligonucleotide retention increases in order C,G,A,T, the oligonucleotide sequence has an impact not only on retention, but also on the success of the target product separation from failure sequences, the hydrophobic contribution of C and G mononucleotides to the oligonucleotide retention is less significant than A and T, and taught the proposed retention model can predict the peak spacing taking into account that the change of oligonucleotide retention with the addition (or loss) of a single mononucleotide correlates with the nucleotide hydrophobicity C,G,A,T, and that the addition of C or G does not increase oligonucleotide retention as dramatically as the addition of A and particularly T.
While Ciaramella et al. in view of CureVac and Gilar et al. does not explicitly teach that each RNA encoding each polypeptide have a harmonized number of A and U nucleotides that is no more than 50 nucleotides, or 20 nucleotides or no more than 10 nucleotides different from each other, one of ordinary skill in the art would be motivated for each RNA encoding the influenza antigens of Ciaramella et al. that if the same modifications are applied to each RNA in the vaccine (increasing G/C content in the coding region and/or increasing A/U content near the ribosome binding site), that there would be a similar number of such modifications applied to each RNA species to fall within the recited limitations regarding the number of added or removed A and U nucleotides in each RNA. In addition, based on the teachings of Gilar et al. regarding that A and T additions increase oligonucleotide retention more dramatically and that change of oligonucleotide retention is affected by the addition or loss of a single mononucleotide which correlates with nucleotide hydrophobicity C,G,A and T, an ordinary artisan would have been motivated to modify the number of A and U nucleotides in each RNA species in order to modify the retention time of the oligonucleotides so that they co-elute as a single overlaid product peak as instantly claimed. Absent demonstration of the criticality of the nucleotide difference, it is concluded that the normal desire of scientists or artisans to improve upon what is generally known would provide motivation to determine where in a disclosed set of ranges is the optimum number of nucleotides different from each other of the harmonized RNA species. Note: MPEP 2144.05.
Accordingly, the limitations of claims 55,71-73,75 and 78-83 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Response to Arguments
Applicant's arguments and amendments filed 07/29/2026 have been fully considered but they are not persuasive.
Applicant argues on page 9 that amended claim 55 requires that the harmonized RNA species have retention times that cause the at least two RNA species to co-elute as a single, overlaid product peak in reversed-phase HPLC for co-purification and/or co-analysis, and is grounded in the specification’s disclosure than A/U-count adaptation is used to harmonize chromatographic retention times of multiple RNA species, and that co-purification by RP-HPLC because feasible when different RNA molecule species elute at essentially the same time point, producing an overlay of product peaks and further explains that altering the number of A and/or U nucleotides modifies retention time and can decrease the separation factor between RNA species, and also describes adapted RNA species eluting together in one fraction or appear in the chromatogram as one single peak, referred to as peak harmonization or harmonization of retention times, and refers to Figures 8A-B and Example 4, Figure 10A and Example 5. Applicant argues this limitation is not taught or suggested by the applied combination, as Ciaramella is relied upon for multivalent influenza RNA vaccines comprising multiple RNA polynucleotides and CureVac is relied upon for modifying mRNA nucleotide content for stability and translation but does not identify any teaching to coordinate the A and U nucleotide counts of different RNA species to those different RNA species have retention times causing co-elution as a single, overlaid peak product in reversed phase HPLC. Applicant argues that CureVac teaches increasing G/C content in a coding region to improve mRNA stability and increasing A/U content around a ribosome binding site to facilitate ribosome binding, and these teachings concern stability and translation of mRNAs, not harmonizing retention times.
Applicant argues that the Action acknowledges that the references do not explicitly teach that the RNA encoding each polypeptide has the claimed harmonized A/U-count relationship, and this proposed modification therefore requires more than applying CureVac’s individual-sequence optimization teachings to Ciaramella’s multicomponent vaccine and requires selecting and coordinating nucleotide counts across different RNA species to obtain a particular chromatographic co-elution result. Applicant argues that the rationale used in the Action regarding “normal desire to optimize nucleotide differences” is insufficient, as routine optimization presupposes that the parameter be optimized was recognized in the art as result-effective for the relevant purpose. The cited art does not establish the number of A and U nucleotides across different RNA species was recognized as a result-effective variable for causing co-elution as a single, overlaid RP-HPLC product peak for co-purification and/or co-analysis.
Applicant argues on page 11 that the Action’s “same modifications” rationale does not bridge the gap to amended claim 55, as CureVac teaching increased G/C content in coding regions is for mRNA stability and increased A/U content near a ribosome binding site is directed to translation, and do not identify the absolute number of A and U nucleotides across different RNA species as a parameter to be coordinated, not do they suggested selecting A/U counts so that different RNAs have sufficiently aligned RP-HPLC retention times to co-elute as a single, overlaid product peak, and applying a general GC-content or Kozak-region modification to different influenza antigen sequences would not predictably harmonized absolute A/U counts or chromatographic retention times across those different RNA species.
Applicant’s arguments regarding the amendment to claim 55 and what the cited art taught are not found persuasive because it is well settled that "any need or problem known in the field of endeavor at the time of invention and addressed by the patent can provide a reason for combining the elements in the manner claimed." KSR Int 'l Co. v. Teleflex Inc., 550 U.S. 398, 420 (2007). As long as some suggestion to combine the elements is provided by the prior art as a whole, the law does not require that they be combined for the reason or advantage contemplated by the inventor. In re Beattie, 974 F.2d 1309, 1312 (Fed. Cir. 1992); In re Kronig, 539 F.2d 1300, 1304 (CCPA 1976). MPEP 2143.01 and 2144 (IV). The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323, 76 USPQ2d 1662, 1685 (Fed. Cir. 2005) ("One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings."); In re Lintner, 458 F.2d 1013, 173 USPQ 560 (CCPA 1972) (discussed below); In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991).
Therefore, if there is a different reason to arrive at the A/U content and arrive at the same structure as instantly claimed, then the amendment adding a “wherein clause” does not affect the structure, and the wherein clause flows from the number of A and U nucleotides that is no more than 50 nucleotides different in the claim, and if there is a reason to manipulate the number of A and U nucleotides, then the claim is still obvious. See MPEP 2111.04 "A '' clause that merely states the result of the limitations in the claim adds nothing to the patentability or substance of the claim." Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1172 (Fed. Cir. 1993).
Nevertheless, the Examiner has provided an additional reference (Gilar et al.) in the 103 rejection to address the new limitation in claim 55 in the interest of compact prosecution.
Claims 74,76,77,84-89 and 91-94 are rejected under 35 U.S.C. 103 as being unpatentable over Ciaramella et al. in view of CureVac and Gilar et al. as applied to claims 55,71-73,75 and 78-83 above, and further in view of Radosevic et al. (US 20130236494, Published 12 Sept 2013).
The teachings of Ciaramella et al. in view of CureVac and Gilar et al. as applied to claims 55,71-73,75 and 78-83 have been described above.
Ciaramella et al. teach an influenza RNA (e.g., mRNA) vaccine of any one of the foregoing paragraphs formulated in a nanoparticle (e.g., a lipid nanoparticle) (page 10, lines 13-14), and a vaccine that includes at least one RNA polynucleotide having an ORF encoding at least one influenza antigenic polypeptide, wherein at least 80% of the uracil in the open reading frame having a chemical modification, and embodiments where 100% of the uracil in the ORF have a N1-methylpseudouridine in the 5-position of the uracil (page 9, lines 4-14).
Ciaramella et al., CureVac and Gilar et al. do not teach at least two RNAs encoding a different Influenza virus NA polypeptide or antigenic fragment thereof, or at least three RNAs each encoding a different HA polypeptide or antigenic fragment thereof or at least three RNAs each encoding a different Influenza virus NA polypeptide or antigenic fragment thereof.
Before the effective filing date, Radosevic et al. teach a vaccine to be used according to the disclosure is preferably a pharmaceutical composition, and usually includes components in addition to the influenza antigens, e.g., it typically includes one or more pharmaceutically acceptable carrier(s) and/or excipient(s) (paragraph 0072). Radosevic et al. teach a seasonal vaccine comprising HA and NA proteins of at least three influenza strains, for use in inducing protection against the three influenza strains and cross-protection against at least one heterologous influenza strain within the same subtype as compared to at least one of the influenza strains, and also against at least one heterosubtypic influenza strain of which no HA and NA antigens are present in the vaccine (paragraph 0035). Radosevic et al. teach an influenza vaccine that comprises HA and NA from an H1N1, an H3N2 and a B strain of influenza, for use in inducing cross-protection against a pandemic or potentially pandemic influenza strain (paragraph 0027), depending on the particular season and on the nature of the antigen included in the vaccine, the influenza antigens may be derived from one or more of the following hemagglutinin subtypes: influenza A H1, H2, H3, H4, H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, H15 or H16; or influenza B; and one or more of the following neuraminidase subtypes: influenza A N1, N2, N3, N4, N5, N6, N7, N8, or N9; or influenza B. For the majority of the HA subtypes, H1-H7 and H9-H12, all combinations with the 9 NA subtypes have been observed. Exemplary important combinations for influenza A comprise, but are not limited to: H1N1, H2N2, H3N2, H3N1, H5N1, H5N2, H7N7, H1N2, H9N2, H7N2, H7N3 and H10N7. Typically, a seasonal influenza vaccine comprises HA and NA of three influenza strains, which nowadays typically include a H1N1, a H3N2 and at least one B strain. Quadrivalent seasonal vaccines typically include antigens from an additional B strain (typically such vaccines comprise antigens from both a Yamagata and from a Victoria lineage B strain) (paragraph 0062).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to have substituted the RNAs encoding each influenza antigen in the vaccine composition of Ciaramella et al. in view of CureVac and Gilar et al. with the specific combinations of influenza antigens of Radosevic et al. with a reasonable expectation of success. There would be a reasonable expectation of success, as Ciaramella et al., CureVac and Radosevic et al. al pertain to vaccines, and Ciaramella et al. and Radosevic et al. pertain to influenza vaccines, and would amount to simple substitution of one known element for another to obtain predictable results.
One of ordinary skill in the art would have been motivated to provide at least two RNAs or at least three RNA’s encoding a different Influenza virus NA polypeptide, or at least three RNAs encoding a different Influenza virus HA polypeptide because Radosevic et al. taught a seasonal vaccine comprising HA and NA proteins of at least three influenza strains, for use in inducing protection against the three influenza strains and cross-protection against at least one heterologous influenza strain and depending on the particular season and on the nature of the antigen included in the vaccine, the influenza antigens may be derived from one or more of the following hemagglutinin subtypes: influenza A H1, H2, H3, H4, H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, H15 or H16; or influenza B; and one or more of the following neuraminidase subtypes: influenza A N1, N2, N3, N4, N5, N6, N7, N8, or N9; or influenza B.
One of ordinary skill in the art would have been motivated to provide at least three RNAs encoding Influenza A and Influenza B HA polypeptides, and wherein the at least three RNAs encode Influenza HA polypeptides from Influenza H1N1 virus, an Influenza H3N2 and an Influenza B virus, or wherein the at least three RNAs encoding Influenza A and Influenza B HA polypeptides, including Influenza HA-A and Influenza HA-B polypeptide, and wherein the at least three RNAs encoding Influenza HA polypeptide from Influenza H1N1 virus, Influenza H3N2 and an Influenza B virus, in the vaccine composition of Ciaramella et al. in view of CureVac, because Radosevic et al. teach an influenza vaccine that comprises HA and NA from an H1N1, an H3N2 and a B strain of influenza, for use in inducing cross-protection against a pandemic or potentially pandemic influenza strain (paragraph 0027), depending on the particular season and on the nature of the antigen included in the vaccine, the influenza antigens may be derived from one or more of the following hemagglutinin subtypes: influenza A H1, H2, H3, H4, H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, H15 or H16; or influenza B; and one or more of the following neuraminidase subtypes: influenza A N1, N2, N3, N4, N5, N6, N7, N8, or N9; or influenza B, and for the majority of the HA subtypes, H1-H7 and H9-H12, all combinations with the 9 NA subtypes have been observed. Exemplary important combinations for influenza A comprise, but are not limited to: H1N1, H2N2, H3N2, H3N1, H5N1, H5N2, H7N7, H1N2, H9N2, H7N2, H7N3 and H10N7. Typically, a seasonal influenza vaccine comprises HA and NA of three influenza strains, which nowadays typically include a H1N1, a H3N2 and at least one B strain. Quadrivalent seasonal vaccines typically include antigens from an additional B strain (typically such vaccines comprise antigens from both a Yamagata and from a Victoria lineage B strain) (paragraph 0062).
Accordingly, the limitations of claims 74,76,77,84-89 and 91-94 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Response to Arguments
Applicant's arguments filed 07/29/2026 have been fully considered but they are not persuasive.
Applicant argues on page 12 that Radosevic does not address RNA sequence adaptation, A/U count harmonization, RP-HPLC retention-time alignment or co-elution and therefor does not cure the deficiency of Ciaramella and Curevac with respect to amended claim 5.
The Examiner has responded to the arguments above in the response to arguments of the previous 103 rejection, and as stated above has provided an additional reference in the rejection to address the claims as amended, and therefore the rejection of claims 74,76,77,84-89 and 91-94 also incorporates the teachings of the new reference (Gilar et al.).
Conclusion
Claims 55,71-89 and 91-94 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/STEPHANIE L SULLIVAN/Examiner, Art Unit 1635
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636
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